ABSTRACT
Antibodies are commonly used in cancer immunotherapy because of their high specificity for tumor-associated antigens. The binding of antibodies can have direct effects on tumor cells but also engages natural killer (NK) cells via their Fc receptor. Mucin 1 (MUC1) is a highly glycosylated protein expressed in normal epithelial cells, while the under-glycosylated MUC1 epitope (MUC1-Tn/STn) is only expressed on malignant cells, making it an interesting diagnostic and therapeutic target. Several anti-MUC1 antibodies have been tested for therapeutic applications in solid tumors thus far without clinical success. Herein, we describe the generation of fully humanized antibodies based on the murine 5E5 antibody, targeting the tumor-specific MUC1-Tn/STn epitope. We confirmed that these antibodies specifically recognize tumor-associated MUC1 epitopes and can activate human NK cells in vitro. Defucosylation of these newly developed anti-MUC1 antibodies further enhanced antigen-dependent cellular cytotoxicity (ADCC) mediated by NK cells. We show that endocytosis inhibitors augment the availability of MUC1-Tn/STn epitopes on tumor cells but do not further enhance ADCC in NK cells. Collectively, this study describes novel fully humanized anti-MUC1 antibodies that, especially after defucosylation, are promising therapeutic candidates for cellular immunotherapy.
ABSTRACT
Open innovation is the new buzz, with initiatives popping up left and right. Here, we give a personal perspective on a very successful, knowledge-driven innovation initiated in an academia- industry alliance, which culminated in technology platforms that enable the generation of therapeutic antibodies with novel properties. To start, we provide a general background on open innovation in the drug development field.
Subject(s)
Antibodies, Monoclonal/therapeutic use , Drug Approval , Drug Design , Animals , HumansABSTRACT
The recombinant antibody fragment Fab GLN 495 recognizes an epitope shared by members of the neuron-associated Hu protein family (including HuC, HuD, and HelNl). This novel reagent labels the nuclei of neurons throughout the peripheral and central neuraxes and has been shown to recognize pulmonary small cell carcinomas and central nervous system (CNS) tumors of mature neuronal phenotype or neuronogenic differentiating capacity. Using this Fab fragment, we have undertaken a systematic survey of normal human tissues and an assessment of 554 non-CNS tumor samples for immunohistochemical evidence of Hu expression. Adrenomedullary cells, pancreatic islet cells, paraganglial chief cells, isolated adenohypophyseal cells, and spermatogonia were the only nonneuronal normal tissue elements to bind Fab GLN 495. In addition to labeling all 10 small cell carcinomas studied (six of which were extrapulmonary in origin), this recombinant anti-Hu Fab proved immunoreactive with neuroblastomas (four/four), esthesioneuroblastomas (one/one), typical (three/four) and atypical (one/four) pulmonary carcinoids, pancreatic islet cell tumors (two/six), large-cell neuroendocrine carcinoma of lung (one/four), Merkel cell tumors (two/three), medullary carcinomas of the thyroid (four/six), pheochromocytomas (two/four) and paragangliomas (four/four). Nonneural/neuroendocrine tumor labeling was restricted to the neuronal and immature neuroepithelial components of teratomas, to extraskeletal myxoid chondrosarcomas (three/four) and to small subsets of cells within examples of renal rhabdoid tumor (one/four), desmoplastic small cell tumor (one/four), alveolar rhabdomyosarcoma (two/four), Ewing sarcoma/PNET (two/nine), and Wilms tumor (one/four). Immunoreactivity was principally nuclear, with variable cytoplasmic labeling. Our findings support the largely restricted expression of Hu by neural/neuroendocrine neoplasms, suggest a potential role for Fab GLN 495 in the identification of small cell carcinomas irrespective of primary site, and support a recent proposal that at least some extraskeletal myxoid "chondrosarcomas" actually represent neuroendocrine tumors of soft parts. Int J Surg Pathol 8(2):109-117, 2000
